The discovery of new materials with novel chemical and physical properties often leads to the development of new and useful technologies. Currently, there is a tremendous amount of activity in the discovery and optimization of materials, such as superconductors, zeolites, magnetic materials, phosphors, nonlinear optical materials, thermoelectric materials, high and low dielectric materials and the like. Unfortunately, even though the chemistry of extended solids has been extensively explored, few general principles have emerged that allow one to predict with certainty the composition, structure and reaction pathways for the synthesis of such solid state compounds.
The preparation of new materials with novel chemical and physical properties is at best happenstance with our current level of understanding. Consequently, the discovery of new materials depends largely on the ability to synthesize and analyze new compounds. Given approximately 100 elements in the periodic table which can be used to make compositions consisting of three, four, five, six or more elements, the universe of possible new compounds remains largely unexplored. As such, there exists a need in the art for a more efficient, economical and systematic approach for the synthesis of novel materials and for the screening of such materials for useful properties.
One of the processes whereby nature produces molecules having novel functions involves the generation of large collections (libraries) of molecules and the systematic screening of those collections for molecules having a desired property. An example of such a process is the humoral immune system which in a matter of weeks sorts through some 10.sup.12 antibody molecules to find one which specifically binds a foreign pathogen (Nisonoff, et al., The Antibody Molecule (Academic Press, New York, 1975)). This notion of generating and screening large libraries of molecules has recently been applied to the drug discovery process. The discovery of new drugs can be likened to the process of finding a key which fits a lock of unknown structure. One solution to the problem is to simply produce and test a large number of different keys in the hope that one will fit the lock.
Using this logic, methods have been developed for the synthesis and screening of large libraries (up to 10.sup.14 molecules) of peptides, oligonucleotides and other small molecules. Geysen, et al., for example, have developed a method wherein peptide syntheses are carried out in parallel on several rods or pins (see, J. Immun. Meth. 102:259-274 (1987), incorporated herein by reference for all purposes). Generally, the Geysen, et al. method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. In addition to the Geysen, et al. method, techniques have recently been introduced for synthesizing large arrays of different peptides and other polymers on solid surfaces. Pirrung, et al., have developed a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques (see, U.S. Pat. No. 5,143,854 and PCT Publication No. WO 90/15070, incorporated herein by reference for all purposes). In addition, Fodor, et al. have developed, among other things, a method of gathering fluorescence intensity data, various photosensitive protecting groups, masking techniques, and automated techniques for performing light-directed, spatially-addressable synthesis techniques (see, Fodor, et al., PCT Publication No. WO 92/10092, the teachings of which are incorporated herein by reference for all purposes).
Using these various methods, arrays containing thousands or millions of different elements can be formed (see, U.S. patent application Ser. No. 08/805,727, filed Dec. 6, 1991, the complete disclosure of which is incorporated herein by reference for all purposes). As a result of their relationship to semiconductor fabrication techniques, these methods have come to be referred to as "Very Large Scale Immobilized Polymer Synthesis," or "VLSIPS.TM." technology. Such techniques have met with substantial success in, for example, screening various ligands such as peptides and oligonucleotides to determine their relative binding affinity to a receptor such as an antibody.
The solid phase synthesis techniques currently being used to prepare such libraries involve the stepwise, i.e., sequential, coupling of building blocks to form the compounds of interest. In the Pirrung, et al. method, for example, polypeptide arrays are synthesized on a substrate by attaching photoremovable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photoremovable group to the activated region, and repeating the steps of activation and attachment until polypeptides of the desired length and sequences are synthesized. These solid phase synthesis techniques, which involve the sequential coupling of building blocks (e.g., amino acids) to form the compounds of interest, cannot readily be used to prepare many inorganic and organic compounds.
Schultz, et al. apply combinatorial chemistry techniques to the field of material science (PCT WO 96/11878, the complete disclosure of which is incorporated herein by reference). More particularly, Schultz, et al. provide methods and apparatus for the preparation and use of a substrate having an array of diverse materials in predefined regions thereon. A substrate having an array of diverse materials thereon is generally prepared by delivering components of materials to predefined regions on the substrate to form different materials. Using the methodology of Schultz, et al., many classes of materials can be generated combinatorially including, for example, inorganic materials, intermetallic materials, metal alloys, ceramic materials, etc. Once prepared, such materials can be screened for useful properties including, for example, electrical, thermal, mechanical, etc.
In the field of pharmaceutical research, high-throughput screening (HTS) protocols have existed for some time for the screening of natural products and archived synthetic libraries. The development of synthetic methods for creating large libraries of organic molecules with possible pharmaceutical relevance has been the final piece of the pharmaceutical combinatorial puzzle, generating much of the recent excitement. While important, the ability to rapidly prepare libraries of polymers is of little value without the ability to rapidly screen materials for properties of interest. This combination of synthetic and screening strategies significantly alters the discovery process for polymers in many commercially important applications, including bulk plastics, imaging systems, thin polymer films, adhesives, polymers for electronic or optical devices, and coatings.
Many aspects of polymer science are well adapted to combinatorial research strategies. Since polymers are generally synthesized from individual monomer units, parallel synthesis strategies, including combinatorial synthesis, will allow exploration of polymer composition by direct combination of different monomers. For practical commercial applications, however, polymer discovery usually requires far more information than the monomer composition alone. Included in this are physical attributes such as hydrogen bonding and other interchain interactions, chain orientation, processing effects, microphase separation, polarity, glass transition temperature, solubility, miscibility, chain mobility, melting temperature, degree of crystallinity, free volume, and physical aging. The effective application of combinatorial methods to polymer science and organic materials discovery requires rapid sample preparations and screening protocols for these properties.
Dyes of various types have been used to probe the attributes of individual chemical and biological systems. Such probes can provide information based on effects of the system of interest on spectral attributes or intensity of dye absorption or fluorescent emission. Such probes can be physically combined with the system of interest, or can be covalently or ionically bound to the system. Some environmentally sensitive dyes provide information related to the system of interest based on dye-dye interactions, while others provide information directly related to the microenvironment of separated dye molecules. One particularly interesting system is based on dyes that link donor fragments and acceptor fragments with a flexible link, typified by the molecule 4-(dimethylaminobenzylidene)malononitrile, and substituted variants. With dyes of this sort, fluorescent behavior of the dye may be affected by the microviscosity of the environment, with viscous environments tending to increase fluorescent quantum yield. (Loutfy, R. O. Macromolecules, 1981, 14, 270-275. Safarzadeh-Amiri, A. Chem. Phys. Lett, 1986, 129, 225, the complete disclosure of which is incorporated herein by reference for all purposes.) The fluorescence can be strongly influenced by temperature, solvent, and environment polarity. It has been shown in one case that the temperature dependence of the fluorescence of a related dye imbedded in a poly(methylmethacrylate) matrix showed a distinct break at the T.sub.g of the polymer matrix. (Loutfy.) One very recent report has described the preparation of a 112 member polymer library as a candidate pool for selecting biomedical implant materials. (Brocchini, S.; James, K.; Tangpasuthadol, V.; Kohn, J. J. Am. Chem. Soc. 1997, 119, 4553-4554.) This library design also allowed for the elucidation of useful structure property relationships. However, this work does not address the need for efficient and rapid characterization of polymers. Conventional, time-consuming characterization of each individual material was carried out, including the use of differential scanning calorimetry (DSC) to measure T.sub.g of each material, a technique that typically requires between 30 minutes to one hour per sample. With the ability to rapidly create many materials in a combinatorial array, such slow, sequential analytical methods become rate-limiting in the materials discovery process. To this end, it would be beneficial to construct apparatus and methodology for screening a substrate having an array of materials that differ slightly in composition, concentrations, stoichiometries and thickness across the substrate.